Angiotensin-converting enzyme (ACE) inhibitors are used to treat high blood pressure and some types of heart failure. Perindopril, (2S)-2-[(1S)-1-carbethoxybutylamino]-1-oxopropyl-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (I), is a potential (ACE) inhibitor. Perindopril erbumine salt is marketed under the brandname ACEON®.

U.S. Pat. No. 4,508,729 and EP 004965881 patents have disclosed Perindopril and its pharmaceutically acceptable salts, wherein pharmaceutically acceptable salt is selected from the group comprising mineral organic, base or acid such as the sodium salt or maleate salt. This patent also disclosed the stability of maleate and sodium salts of Perindopril. In the course of stability studies towards temperature and humidity, it is found that sodium salt is not suitable for making the formulation because it is immediately converted into oil on contact with the atmosphere. With respect to the maleate salt, it degrades rapidly under such conditions (approximately 25 to 30% of product degraded in 8 days at 50° C.).
U.S. Pat. No. 4,914,214 discloses a process for the preparation of Perindopril and its tert-butylamine salt (Perindopril erbumine). The tert-butylamine salt has exhibited the best stability compared to the other salts studied till then. But, in view of the intrinsic fragility of Perindopril, the tert-butylamine salt has not been capable of providing a complete solution to the problems of the product's stability towards heat and humidity. Indeed, for marketing tablets of Perindopril tert-butylamine salt in certain countries, additional packaging is found to be essential. Moreover, even for temperate-climate countries, the instability of the product has made it impossible to obtain a shelf-life of more than 2 years for the tablets. Finally, for marketing the tablets, they have to be marked “to be stored at a temperature less than or equal to 30 degrees”.
According to the prior art, Perindopril, tert-butylamine salt is stored in a special package and requires appropriate storage conditions, thus making it a costly issue. Thus, there is a need to develop a new salt, which is having good stability in different temperatures and humidity conditions.
Numerous salts were studied and, as indicated hereinbefore, the salts customarily used in the pharmaceutical sector proved to be unstable. On the other hand, and in surprising manner, it has been found that the Arginine salt of Perindopril, besides being new, has many unexpected advantages over all the other salts studied so far, especially, over the tert-butylamine salt of Perindopril.
Perindopril Arginine represented by the formula (II), its hydrates, pharmaceutical composition and a method of treatment is first disclosed in U.S. Pat. No. 6,696,481. This patent also disclosed that the Arginine salt of Perindopril is an alternate to tert-butylamine salt having superior properties in terms of stability towards heat and humidity.
US '481 patent does not disclose the experimental details for preparation of the hydrates of Arginine salt of Perindopril. The said hydrates are not characterized by moisture content, DSC and PXRD pattern. In addition to this, the said patent claims Arginine salt of Perindopril and hydrates thereof.
WO 2007099216 claims beta (β) crystalline polymorphic form of (L)-Arginine salt of Perindopril and process for the preparation thereof.
WO 2007099217 claims alpha (α) crystalline form of the (L)-Arginine salt of Perindopril and process for the preparation thereof.
WO '216 and WO '217 patent applications provided 2θ, d-spacing values and intensity table for Form α and Form β but no PXRD pattern is disclosed. These applications further provides insufficient experimental details in each case by disclosing only a single example (example-1) for preparation of Form α and Form β.
According to WO '217 English translation, in Example 1, crystalline Form α is prepared by dissolving 1:1 molar ratio of Perindopril and (L)-Arginine in water at ambient temperature under stirring, followed by addition of methylcyclohexane and then dimethylsulfoxide. The solution is cooled to 20° C. and maintained under stirring. The solid obtained is filtered, washed and dried. The reproduction of Example 1 of WO'217 in our laboratories afforded Form α inconsistently (success rate 10%) with characteristic peaks as disclosed in WO '217 application (FIG. 3). We further simulated the PXRD pattern of Form α from the literature data (WO '217 PXRD table) which is similar to our experimental PXRD pattern (FIG. 4). The water content of the experimental Form α is in the range of 3-4% which further confirms that the form α is a hydrate, preferably monohydrate.
According to WO '216 English translation, Example 1, crystalline Form β is prepared by dissolving the salt of (L)-Arginine of Perindopril in acetonitrile at reflux temperature. After 1 hour stirring under reflux, the crystals obtained are filtered at a temperature of 80° C. The crystals obtained are dried, which leads to Form β in anhydrous form. However, the reproduction of Example 1 of WO'216 in our laboratories never obtained Form β. Also we attempted several other process variations for the preparation of Form β such as starting from 1:1 molar ratios of Perindopril and (L)-Arginine or from Perindopril (L)-Arginine salt using different solvent combinations at different temperatures but we failed to reproduce Form β.
According to WO '216 crystalline form β is an anhydrous form which prompted us to look at several other processes techniques to remove moisture from Form α (monohydrate) such as azeotropic distillation and/or by drying. But even after reducing the moisture content below 1% (Table-2) we failed to obtain Form β. From this it appears that WO'216 application process is not suitable for the preparation of form β or polymorphic form β in an elusive form.
In view of the above prior problems, there is an unmet need for a stable form of Perindopril (L)-Arginine which can be prepared by an efficient, economic and reproducible process, particularly to large scale preparation. Further it should be suitable for handling and have excellent physical and chemical stability towards heat and humidity at different conditions.
Amorphous forms of an API are characterized by decreasing amounts of long range order in the solid state and may enjoy enhanced properties with respect to crystalline forms of the solid. Also relevant is the degree of amorphous character. Crystallinity and amorphicity are continuous properties and a particular solid may have a degree of crystallinity that ranges from 0% (fully amorphous) to 100% (fully crystalline). The structural basis for losses in crystallinity could arise from progressive “decrystallization” throughout the solid or through a growth of amorphous regions within the crystalline matrix (Polymorphism: in the Pharmaceutical Industry, R. Hilfiker (Ed.), Wiley-VCH, Weinheim, Chapter 10, pp. 259-285, 2006). It is noted that no amorphous forms of Perindopril (L)-Arginine are satisfactorily characterized.